Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Bassil, Fares; Fernagut, Pierre‐Olivier; Bézard, Erwan; Pruvost, Alain; Lesté-Lasserre, Thierry; Hoang, Quyen Q.; Ringe, Dagmar; Petsko, Gregory A.; Meissner, Wassilios G.

doi:10.1073/pnas.1609291113

Cited by 95 publications

(91 citation statements)

References 65 publications

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“…PLP‐hαSyn mice also develop progressive SND characterized by a 30% reduction in the number of dopaminergic neurons (tyrosine hydroxylase positive [TH + ] neurons) in the SNc compared to healthy control animals. This neuronal loss is already present at 4 months of age and is followed by a significant reduction in density of dopaminergic terminals and in number of medium spiny neurons in the striatum at 12 months of age . SN and striatum are both essential for motor control, and the loss of neurons in these two brain areas leads to motor impairment in these mice …”

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confidence: 99%

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

Heras‐Garvin

Weckbecker²,

Ryazanov

et al. 2018

Movement Disorders

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Background MSA is a fatal neurodegenerative disease characterized by autonomic failure and severe motor impairment. Its main pathological hallmark is the accumulation of α‐synuclein in oligodendrocytes, leading to glial and neuronal dysfunction and neurodegeneration. These features are recapitulated in the PLP‐hαSyn mouse model expressing human α‐synuclein in oligodendrocytes. At present, there is no effective disease‐modifying therapy. Previous experiments have shown that the aggregation inhibitor, anle138b, reduces neurodegeneration and behavioral deficits in mouse models of other proteinopathies. Objectives To test the therapeutic potential of anle138b in a mouse model of MSA. Methods Two‐month‐old PLP‐hαSyn mice were fed over a period of 4 months with pellets containing anle138b at two different doses (0.6 and 2 g/kg) and compared to healthy controls and PLP‐hαSyn mice fed with placebo pellets. At the end of the treatment, behavioral and histological analyses were performed. Results We observed a reversal of motor function to healthy control levels when PLP‐hαSyn mice were treated with both doses of anle138b. Histological and molecular analyses showed a significant reduction in α‐synuclein oligomers and glial cytoplasmic inclusions in animals fed with anle138b compared to nontreated mice. These animals also present preservation of dopaminergic neurons and reduction in microglial activation in SN correlating with the α‐synuclein reduction observed. Conclusions Anle138b reduces α‐synuclein accumulation in PLP‐hαSyn mice, leading to neuroprotection, reduction of microglial activation, and preservation of motor function supporting the use of anle138b in a future clinical trial for MSA. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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confidence: 99%

Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

Heras‐Garvin

Weckbecker²,

Ryazanov

et al. 2018

Movement Disorders

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“…Therefore, a caspase‐1 inhibitor could exert neuroprotective effects on synucleinopathies by reducing αSyn cleavage, hence limiting its toxicity and its ability to form aggregates. An in vivo proof of concept of the ability of a caspase‐1 inhibitor to mitigate αSyn pathology and to mediate neuroprotection in a pathologic and phenotypic transgenic mouse model of MSA, the PLP‐SYN mice, was conducted and showed that such caspase‐1 inhibition prevented motor deficits in PLP‐SYN mice compared with placebo controls . More importantly, caspase‐1 inhibition was able to limit the progressive toxicity of αSyn aggregation by reducing its load in the striatum of PLP‐SYN mice .…”

Section: Discussionmentioning

confidence: 99%

“…An in vivo proof of concept of the ability of a caspase‐1 inhibitor to mitigate αSyn pathology and to mediate neuroprotection in a pathologic and phenotypic transgenic mouse model of MSA, the PLP‐SYN mice, was conducted and showed that such caspase‐1 inhibition prevented motor deficits in PLP‐SYN mice compared with placebo controls . More importantly, caspase‐1 inhibition was able to limit the progressive toxicity of αSyn aggregation by reducing its load in the striatum of PLP‐SYN mice . Not only did caspase‐1 inhibition reduce truncated αSyn but also decreased its monomeric and oligomeric forms .…”

Section: Discussionmentioning

confidence: 99%

Targeting α‐synuclein: Therapeutic options

et al. 2016

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The discovery of the central role of α-synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector-mediated expression of the disease-causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal-autophagic system, through proteasome-mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society.

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“…Here, the companion paper by Bassil et al (2) furthers our understanding of how caspase-1-mediated truncation, oligomerization, and aggregation of αSyn in glia may mediate neurotoxicity in vivo. Bassil et al (2) studied PLP-SYN tg mice, in which the promoter of the myelin-associated proteolipid protein (PLP) drives αSyn overexpression in oligodendrocytes and thereby models key aspects of MSA, including GCIs, neuroinflammation, dopaminergic cell loss, and motor deficits (22).…”

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confidence: 89%

“…Scientists have begun identifying factors that may initiate or accelerate αSyn aggregation and how this process relates to progressive impairment of neuronal structure and function. In PNAS, companion papers by Wang et al (1) and Bassil et al (2) establish a compelling link between the accumulation of C-terminally truncated forms of αSyn created by caspase-1 and cellular dysfunction in culture and in vivo, all potentially initiated by inflammatory insults.…”

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confidence: 99%